Type 1 diabetes (T1D) in both humans and NOD mice results from T cell mediated autoimmune destruction of insulin producing pancreatic Beta cells. While controlled by multiple susceptibility (Idd) genes, particular MHC haplotypes provide the primary risk factor for T1D. Within the MHC, unusual class II alleles clearly contribute to T1D by mediating the selection and activation of Beta cell autoreactive CD4 T cells. However, T1D fails to develop in beta2-microglobulin deficient NOD mice that lack MHC class I expression and CD8 T cells. Thus, while they represent common alleles shared by many strains without obvious autoimmune proclivity, the Kd and/or Db class I gene products encoded by the H2g7 MHC haplotype of NOD mice also play an essential diabetogenic role. Our overall goal is to understand under what circumstances common, normally non-pathogenic, MHC class I variants acquire an aberrant ability to mediate autoreactive diabetogenic CD8 T cell responses. Preliminary data indicate that some of the many other Idd genes contributing to T1D susceptibility in NOD mice may interactively elicit defects that result in a failure to negatively select diabetogenic CD8 T cells. Our first aim is to map the non-MHC genes that interactively impair the ability of NOD mice to negatively select diabetogenic CD8 T cells which recognize Beta cell autoantigens presented by the common class I variants of H2 g7 MHC haplotype. Aim 2 is to identify mechanisms controlled by non-MHC genes that underlie the defective intra-thymic deletion of diabetogenic CD8 T cells in NOD mice. There is also evidence that when expressed in the proper genetic context, some common human MHC class I variants, such as HLA-A2.1, aberrantly contribute to T1D development. Supporting this possibility was our finding that when transgenically expressed in NOD mice, human HLA-A2.1 molecules mediate Beta cell autoreactive CD8 T cell responses causing accelerated T1D development. The antigenic peptides presented by transgenic HLA-A2.1 molecules to murine CD8 T cells overlap those presented to human CD8 T cells by endogenously encoded HLA-A2.1 molecules. Hence, our third aim is to determine the repertoire of diabetogenic CD8 T cell responses that are mediated by transgenically expressed human HLA-A2.1 class I molecules in NOD mice.